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RELATIONSHIP BETWEEN SYSTEMIC AND CENTRAL NERVOUS SYSTEM MONOCYTE/MACROPHAGE INFECTION IN SIMIAN IMMUNODEFICIENCY VIRUS ENCEPHALITIS

Bissel, Stephanie Jane (2006) RELATIONSHIP BETWEEN SYSTEMIC AND CENTRAL NERVOUS SYSTEM MONOCYTE/MACROPHAGE INFECTION IN SIMIAN IMMUNODEFICIENCY VIRUS ENCEPHALITIS. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Approximately ¼ of AIDS patients develop HIVE, the pathologic entity associated with cognitive, motor, and behavioral deficits attributed to synaptic damage and neuronal loss. It still remains unclear why only a subset of HIV-infected individuals develops abundant central nervous system (CNS) macrophage/microglia infection that characterizes HIVE. The overarching hypothesis of this body of work is that simian immunodeficiency virus (SIV) encephalitis (SIVE) is the CNS manifestation of a systemic increase in SIV infection and activation of monocyte/macrophage elements. Specifically, we examined the relationship of infected and activated monocyte/macrophage elements outside of the CNS during the evolution of lentiviral encephalitis to the presence of infected macrophages in the CNS. We studied three models of SIV infection: SIV-infection of rhesus and pigtailed macaques and SIV-infection of CD8+ T cell depleted macaques. Antibody-mediated CD8+ T cell depletion did not increase the incidence of SIVE in infected rhesus macaques. In SIV-infected rhesus macaques, we examined whether presence of activated macrophages or SIV-infected macrophages is associated with the presence of neuronal damage. The presence of abundant infected macrophages in the CNS is related to postsynaptic neuronal damage in macaques with SIVE. At the same time cerebrospinal fluid viral load increased in SIV-infected CD8-depleted rhesus and non-depleted pigtailed macaques that developed encephalitis, monocyte-derived macrophages produced more virus ex vivo than macaques that did not develop encephalitis. Compared to pigtailed macaques that did not develop SIVE, the monocyte associated SIV-DNA load of monocytes was elevated in macaques that developed SIVE. Pigtailed macaques with SIVE had more infected macrophages in peripheral organs, with the exception of lymph nodes, than macaques without SIVE. Longitudinal analysis of phenotypic markers of monocyte activation show that increases in proportion of CD14+/CD16+ monocytes is associated with chronic disease. Brains with SIVE have greater numbers of T cells with cytotoxic potential. In conclusion, these findings suggest that inherent differences in host macrophage viral production or immune response to macrophage infection are associated with development of encephalitis. Further understanding of the differential role monocyte/macrophages have in the development of lentiviral encephalitis will identify therapeutic targets to halt this public health epidemic.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Bissel, Stephanie Janesjbissel@mac.com
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairWiley, Clayton Aclaytonwiley@comcast.net
Committee CoChairBarratt-Boyes, Simonsmbb@pitt.eduSMBB
Committee MemberMurphey-Corb, Michaelmcorb@pitt.eduMCORB
Committee MemberMontelaro, Ronald Crmont@pitt.eduRMONT
Date: 3 February 2006
Date Type: Completion
Defense Date: 29 November 2005
Approval Date: 3 February 2006
Submission Date: 9 December 2005
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Institution: University of Pittsburgh
Schools and Programs: Graduate School of Public Health > Infectious Diseases and Microbiology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: brain; central nervous system; encephalitis; human immunodeficiency virus; macrophage; monocyte; pathology; simian immunodeficiency virus
Other ID: http://etd.library.pitt.edu/ETD/available/etd-12092005-145928/, etd-12092005-145928
Date Deposited: 10 Nov 2011 20:09
Last Modified: 15 Nov 2016 13:54
URI: http://d-scholarship.pitt.edu/id/eprint/10248

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